Original Article

Leukemia (2014) 28, 2222–2228; doi:10.1038/leu.2014.130; published online 16 May 2014

Silencing AML1-ETO gene expression leads to simultaneous activation of both pro-apoptotic and proliferation signaling

P V Spirin1,8, T D Lebedev1,8, N N Orlova1,2,8, A S Gornostaeva1,2, M M Prokofjeva1, N A Nikitenko1, S E Dmitriev1,3, A A Buzdin4,5,6, N M Borisov5,6, A M Aliper4,5, A V Garazha5,6, P M Rubtsov1, C Stocking7 and V S Prassolov1,2

  1. 1Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
  2. 2Moscow Institute of Physics and Technology, Dolgoprudny, Russia
  3. 3Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia
  4. 4Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia
  5. 5D Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
  6. 6Pathway Pharmaceuticals Limited, Wan Chai, Hong Kong Special Administrative Region
  7. 7Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany

Correspondence: VS Prassolov, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32, Vavilova Str., Moscow 119991, Russia. E-mail: prassolov45@mail.ru

8These three authors contributed equally to this work.

Received 2 April 2014; Accepted 7 April 2014
Accepted article preview online 14 April 2014; Advance online publication 16 May 2014



The t(8;21)(q22;q22) rearrangement represents the most common chromosomal translocation in acute myeloid leukemia (AML). It results in a transcript encoding for the fusion protein AML1-ETO (AE) with transcription factor activity. AE is considered to be an attractive target for treating t(8;21) leukemia. However, AE expression alone is insufficient to cause transformation, and thus the potential of such therapy remains unclear. Several genes are deregulated in AML cells, including KIT that encodes a tyrosine kinase receptor. Here, we show that AML cells transduced with short hairpin RNA vector targeting AE mRNAs have a dramatic decrease in growth rate that is caused by induction of apoptosis and deregulation of the cell cycle. A reduction in KIT mRNA levels was also observed in AE-silenced cells, but silencing KIT expression reduced cell growth but did not induce apoptosis. Transcription profiling of cells that escape cell death revealed activation of a number of signaling pathways involved in cell survival and proliferation. In particular, we find that the extracellular signal-regulated kinase 2 (ERK2; also known as mitogen-activated protein kinase 1 (MAPK1)) protein could mediate activation of 23 out of 29 (79%) of these upregulated pathways and thus may be regarded as the key player in establishing the t(8;21)-positive leukemic cells resistant to AE suppression.